Primary open-angle glaucoma (POAG) is an intraocular pressure (IOP)-dependent, slowly progressive optic neuropathy that ultimately leads to blindness. Data from population-based surveys demonstrate that vascular dysfunction, as assessed with ocular hemodynamic testing, measurements of ocular perfusion pressure and markers of vascular endothelial dysfunction, is important in glaucoma. Furthermore, female reproductive attributes, as assessed by age at menopause and postmenopausal hormone use, may also play a role in POAG. In this Resubmission:, we propose to further explore important findings from the previously funded work, by examining key gene environment interactions of vascular dysfunction and estrogen levels in relation to POAG. For the study of vascular dysfunction, we intend to use pre-existing high density whole genome-wide genotyping data from 5 studies (Nurses Health Study [NHS], Health Professionals Follow-up Study [HPFS], Mass Eye and Ear Infirmary, Women's Health Study [WHS] and the NEIGHBOR consortium) to select a panel of markers in genes specifially involved in mediating vascular tone, and identify the top single nucleotide polymorphisms (SNPs) associated with POAG. Second, we will extend the follow-up of NHS and HPFS participants to 2014, and study the relation between biomarkers of endothelial dysfunction (ICAM-1, E-selectin and TNF alpha) and incident POAG, using a nested case control group. Finally, we will assess whether the top SNPs mediating vascular tone interact with biomarkers of endothelial dysfunction in POAG using a case control group from NHS and HPFS. Since estrogen influences vascular tone, we will also assess interactions between the top SNPs mediating vasuclar tone and attributes of female reproduction (see below), among women in the NHS and WHS. To further explore gender biology we propose a prospective cohort study to assess the relationship between female reproductive attributes (age at menarche, parity and oral contraceptive use) and POAG risk among NHS participants. Then, we will evaluate the role of genes in the estrogen- metabolizing pathway, by using the pre-existing high density whole genome-wide genotyping data from the 5 studies. Finally, as gene-environment interactions that influence estrogen levels may be involved in POAG, we plan to ascertain whether the top estrogen metabolizing SNPs interact with various attributes of female reproductive health among women in the NHS and WHS. The discovery of the combination of genetic and environment factors that serve to link gender biology and vascular dysfunction to POAG could lead to more rationale treatments for the disease. Furthermore, this research could lead to genotype-specific lifestyle modification strategies to prevent POAG. PUBLIC HEALTH RELEVANCE: The overall goal of this research is to assess the relation between vascular dysfunction, gender biology and primary open angle glaucoma (POAG), the most common form of glaucoma in the Western world and a leading cause of blindness. We will use 5 datasets with detailed genotype and phenotype information to accelerate the discovery of gene- environment interactions in POAG that are related to vascular tone and estrogen metabolism. The discovery of the combination of genetic and environment factors that link vascular dysfunction, gender biology and POAG could lead to more effective treatments for this potentially blinding condition.